A Transcriptomic Signature of the Hypothalamic Response to Fasting and BDNF Deficiency in Prader-Willi Syndrome

Elena G Bochukova; Katherine Lawler; Sophie Croizier; Julia M Keogh; Nisha Patel; Garth Strohbehn; Kitty K Lo; Jack Humphrey; Anita Hokken-Koelega; Layla Damen; Stephany Donze; Sebastien G Bouret; Vincent Plagnol; I Sadaf Farooqi

doi:10.1016/j.celrep.2018.03.018

A Transcriptomic Signature of the Hypothalamic Response to Fasting and BDNF Deficiency in Prader-Willi Syndrome

Cell Rep. 2018 Mar 27;22(13):3401-3408. doi: 10.1016/j.celrep.2018.03.018.

Authors

Affiliations

¹ University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK; The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK. Electronic address: e.bochukova@qmul.ac.uk.
² University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
³ The Saban Research Institute, Developmental Neuroscience Program, and Diabetes and Obesity Program, Children's Hospital Los Angeles, Center for Endocrinology, Diabetes and Metabolism, University of Southern California, Los Angeles, CA 90027, USA; Inserm, Jean-Pierre Aubert Research Center, U1172, University Lille 2, Lille, 59045, France; Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
⁴ The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
⁵ University College London Genetics Institute (UGI), Department of Genetics, Environment and Evolution, University College London, Darwin Building, Gower Street, London, WC1E 6BT, UK.
⁶ University College London Genetics Institute (UGI), Department of Genetics, Environment and Evolution, University College London, Darwin Building, Gower Street, London, WC1E 6BT, UK; Department of Neurodegenerative Disease, University College London Institute of Neurology, London, WC1N 3BG, UK.
⁷ Erasmus University Medical Center, Rotterdam, the Netherlands; Dutch Growth Research Foundation, Rotterdam, the Netherlands.
⁸ The Saban Research Institute, Developmental Neuroscience Program, and Diabetes and Obesity Program, Children's Hospital Los Angeles, Center for Endocrinology, Diabetes and Metabolism, University of Southern California, Los Angeles, CA 90027, USA; Inserm, Jean-Pierre Aubert Research Center, U1172, University Lille 2, Lille, 59045, France.
⁹ University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. Electronic address: isf20@cam.ac.uk.

Abstract

Transcriptional analysis of brain tissue from people with molecularly defined causes of obesity may highlight disease mechanisms and therapeutic targets. We performed RNA sequencing of hypothalamus from individuals with Prader-Willi syndrome (PWS), a genetic obesity syndrome characterized by severe hyperphagia. We found that upregulated genes overlap with the transcriptome of mouse Agrp neurons that signal hunger, while downregulated genes overlap with the expression profile of Pomc neurons activated by feeding. Downregulated genes are expressed mainly in neuronal cells and contribute to neurogenesis, neurotransmitter release, and synaptic plasticity, while upregulated, predominantly microglial genes are involved in inflammatory responses. This transcriptional signature may be mediated by reduced brain-derived neurotrophic factor expression. Additionally, we implicate disruption of alternative splicing as a potential molecular mechanism underlying neuronal dysfunction in PWS. Transcriptomic analysis of the human hypothalamus may identify neural mechanisms involved in energy homeostasis and potential therapeutic targets for weight loss.

Keywords: Agrp; BDNF; Prader-Willi syndrome; SNORD116; hypothalamus; obesity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain-Derived Neurotrophic Factor / deficiency*
Brain-Derived Neurotrophic Factor / genetics
Brain-Derived Neurotrophic Factor / metabolism
Fasting / physiology*
Humans
Hypothalamus / metabolism*
Mice
Obesity / metabolism
Prader-Willi Syndrome / genetics*
Prader-Willi Syndrome / metabolism*
Prader-Willi Syndrome / pathology
Transcriptome

Substances

Bdnf protein, mouse
Brain-Derived Neurotrophic Factor
BDNF protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding